Pathology Flashcards
What is ARDS? (acute respiratory distress syndrome)
Acute respiratory distress syndrome is a condition of severe diffuse alveolar wall damage. It starts suddenly and leads to severe respiratory insufficiency. Can lead to multi-system organ failure.
Also referred to as severe acute lung injury.
Characteristics: increased vascular permeability, severe epithelial (alveoli) and endothelial (vascular) cell death (reminder alveoli and capillaries share basal membrane)
What are some of the causes of ARDS?
- sepsis
- diffuse pulmonary infections
- gastric aspiration (GERD)
- mechanical trauma
- _____________________ = top
- inhaled irritant - for instance oxygen in high doses, smoke
- near drowining
- burns
- radiation
- heroin and methadone overdose
- ASA
- barbiturates
- paraquat (herbicide)
- pancreatitis
- uremia
- cardiopulmonary bypass
- *
What happens in ARDS
microscopically?
macroscopically?
Macroscopically:
lungs are heavy, firm, red, and boggy (like liver!)
Microscopical:
some alveoli open, some collapsed, many lined with hyaline membranes
congestion, interstitial and intra-alveolar edema, inflammation, fibrin deposition, and diffuse alveolar damage. The alveolar walls become lined with waxy hyaline membranes.
Staging
Exudative stage: edema in alveoli and interstitial fluid, cell necrosis, hyaline membranes
Organizing/healing phase: type II pneumocytes fill up spaces (want to restore alveoli), may eventially differentiate into type I
sometimes minimal damage and all resolves, but sometimes a lot of collagen deposition and thus permanent damage.
Pathogenesis:
“gram -ve sepsis model”
The alveolar capillary membrane is formed by two separate barriers: the microvascular endothelium and the alveolar epithelium. In ARDS the integrity of this barrier is compromised by either endothelial or epithelial injury or, more commonly, both.
Evidence of epithelial injury in the form of swelling, vacuolization, bleb formation, and frank necrosis is also noted early in the course of acute lung injury. The acute consequences of damage to the alveolar capillary membrane include increased vascular permeability and alveolar flooding, loss of diffusion capacity, and widespread surfactant abnormalities caused by damage to type II pneumocytes. Endothelial injury also triggers the formation of microthrombi that add the insult of ischemic injury. Hyaline membranes so characteristic of ALI/ARDS result from heating of protein rich edema fluid that entraps debris of dead alveolar epithelial cells.
Pro-inflammatory cytokines such as IL-1, IL-8 and TNF (released by nonocytes and macrophages) - > activates complement system (C5a -> adhesion molecules up) -> neutrophils adhere to endothelium, extravasate -> end up in alveoli where they cause damage (cell damage, surfactant inactivation) as they release their proteases, oxidants, etc -> damage activates fibroblasts which deposit collagen around alveoli
neutrophils key in this model - there is a huge number of them in alveoli in ARDS, full mechanism why unknown. the body could step up and downregulate this inflammation, but in ARDS it doesn’t
as tissue heals, it upregulates type II pneumocytes (since surfactant was damaged), which can then slowly become type I again
What is pneumonia?
Pneumonia is a generic term to mark inflammation of the pulmonary parenchyma. often present with lung consolidation (solidification). usually infectious in origin.
What are some ways to classify pneumonia?
Anatomical:
lobar pneumonia (bacterial)
bronchopneumonia
interstitial pneumonia (viral)
Clinical:
community acquired pneumonia
nosocomial pneumonia
aspiration pneumonia
pneumonia in immunocompromised
Etiology:
bacterial
viral
other: fungal, pneumocystis, rickettsial, chlamydial, etc - some are bacterial but atypical
List infectious causes for different types of pneumonia?
COMMUNITY-ACQUIRED ACUTE PNEUMONIA
Streptococcus pneumoniae
Haemophilus influenzae
Moraxella catarrhalis
Staphylococcus aureus
Legionella pneumophila
Enterobacteriaceae (Klebsiella pneumoniae) and Pseudomonasspp.
COMMUNITY-ACQUIRED ATYPICAL PNEUMONIA
** Mycoplasma pneumoniae
Chlamydia spp. (C. pneumoniae, C. psittaci, C. trachomatis)
Coxiella burnetii (Q fever)
Viruses: respiratory syncytial virus, parainfluenza virus (children); influenza A and B (adults); adenovirus (military recruits); SARS virus
**
HOSPITAL-ACQUIRED PNEUMONIA
** Gram-negative rods, Enterobacteriaceae (Klebsiella spp., Serratia marcescens, Escherichia coli) and Pseudomonasspp.
Staphylococcus aureus (usually penicillin resistant)
PNEUMONIA IN THE IMMUNOCOMPROMISED HOST
Cytomegalovirus
Pneumocystis jiroveci
Mycobacterium avium-intracellulare
Invasive aspergillosis
Invasive candidiasis
“Usual” bacterial, viral, and fungal organisms (listed above)
**
ASPIRATION PNEUMONIA
Anaerobic oral flora (Bacteroides, Prevotella, Fusobacterium, Peptostreptococcus), admixed with aerobic bacteria (Streptococcus pneumoniae,Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa)
CHRONIC PNEUMONIA
** Nocardia
Actinomyces
Granulomatous: Mycobacterium tuberculosis and atypical mycobacteria, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis
**
NECROTIZING PNEUMONIA AND LUNG ABSCESS
** Anaerobic bacteria (extremely common), with or without mixed aerobic infection
Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pyogenes, and type 3 pneumococcus (uncommon)
**
What are some predisposing factors for pneumonia?
- Loss or suppression of the cough reflex, as a result of coma, anesthesia, neuromuscular disorders, drugs, or chest pain (may lead toaspiration of gastric contents)
- Injury to the mucociliary apparatus, by either impairment of ciliary function or destruction of ciliated epithelium, due to cigarette smoke, inhalation of hot or corrosive gases, viral diseases, or genetic defects of ciliary function
- Accumulation of secretions in conditions such as cystic fibrosis and bronchial obstruction
- Interference with the phagocytic or bactericidal action of alveolar macrophages by alcohol, tobacco smoke, anoxia, or oxygen intoxication
- Pulmonary congestion and edema
Extra info on bacterial pneumonia…
Streptococcus pneumoniae
Streptococcus pneumoniae, or pneumococcus, is the most common cause of community-acquired acute pneumonia. Examination of Gram-stained sputum is an important step in the diagnosis of acute pneumonia. The presence of numerous neutrophils containing the typical gram-positive, lancet-shaped diplococci supports the diagnosis of pneumococcal pneumonia, but it must be remembered that S. pneumoniae is a part of the endogenous flora in 20% of adults, and therefore false-positive results may be obtained. Isolation of pneumococcifrom blood cultures is more specific but less sensitive (in the early phase of illness, only 20% to 30% of patients have positive blood cultures). Pneumococcal vaccines containing capsular polysaccharides from the common serotypes are used in patients at high risk.
Haemophilus influenzae
Haemophilus influenzae is a pleomorphic, gram-negative organism that is a major cause of life-threatening acute lower respiratory tract infections and meningitis in young children. In adults it is a very common cause of community-acquired acute pneumonia.[122] This bacterium is a ubiquitous colonizer of the pharynx, where it exists in two forms: encapsulated (5%) and unencapsulated (95%). Typically, the encapsulated form dominates the unencapsulated forms by secreting an antibiotic called haemocin that kills the unencapsulated H. influenzae.[123] Although there are six serotypes of the encapsulated form (types a to f), type b, which has a polyribosephosphate capsule, used to be the most frequent cause of severe invasive disease. With routine use of H. influenzae conjugate vaccines, the incidence of disease caused by the b serotype has declined significantly. By contrast, infections with nonencapsulated forms are increasing. Also called nontypeable forms, they spread along the surface of the upper respiratory tract and produce otitis media (infection of the middle ear), sinusitis, and bronchopneumonia.
Pili on the surface of H. influenzae mediate adherence of the organisms to the respiratory epithelium.[124] In addition, H. influenzae secretes a factor that disorganizes ciliary beating and a protease that degrades IgA, the major class of antibody secreted into the airways. Survival of H. influenzae in the bloodstream correlates with the presence of the capsule, which, like that of pneumococcus, prevents opsonization by complement and phagocytosis by host cells. Antibodies against the capsule protect the host from H. influenzae infection; hence the capsular polysaccharide b is incorporated in the vaccine against H. influenzae used for children.
H. influenzae pneumonia, which may follow a viral respiratory infection, is a pediatric emergency and has a high mortality rate. Descending laryngotracheobronchitis results in airway obstruction as the smaller bronchi are plugged by dense, fibrin-rich exudate of polymorphonuclear cells, similar to that seen in pneumococcal pneumonias. Pulmonary consolidation is usually lobular and patchy but may be confluent and involve the entire lung lobe. Before a vaccine became widely available, H. influenzae was a common cause of suppurative meningitis in children up to 5 years of age. H. influenzae also causes an acute, purulent conjunctivitis (pink eye) in children and, in predisposed older patients, may cause septicemia, endocarditis, pyelonephritis, cholecystitis, and suppurative arthritis. H. influenzae is the most common bacterial cause of acute exacerbation of COPD.
Moraxella catarrhalis
Moraxella catarrhalis is being increasingly recognized as a cause of bacterial pneumonia, especially in the elderly. It is the second most common bacterial cause of acute exacerbation of COPD. Along with S. pneumoniae and H. influenzae, M. catarrhalis constitutes one of the three most common causes of otitis media in children.
Staphylococcus aureus
Staphylococcus aureus is an important cause of secondary bacterial pneumonia in children and healthy adults following viral respiratory illnesses (e.g., measles in children and influenza in both children and adults). Staphylococcal pneumonia is associated with a high incidence of complications, such as lung abscess and empyema. Intravenous drug abusers are at high risk of developing staphylococcal pneumonia in association with endocarditis. It is also an important cause of hospital-acquired pneumonia, as will be discussed later.
Klebsiella pneumoniae
Klebsiella pneumoniae is the most frequent cause of gram-negative bacterial pneumonia. It commonly afflicts debilitated and malnourished people, particularly chronic alcoholics. Thick and gelatinous sputum is characteristic, because the organism produces an abundant viscid capsular polysaccharide, which the patient may have difficulty expectorating.
Pseudomonas aeruginosa
Although Pseudomonas aeruginosa most commonly causes hospital-acquired infections, it is mentioned here because of its occurrence in cystic fibrosis patients. It is common in patients who are neutropenic and it has a propensity to invade blood vessels with consequent extrapulmonary spread.Pseudomonas septicemia is a very fulminant disease.
Legionella pneumophila
Legionella pneumophila is the agent of Legionnaires’ disease, an eponym for the epidemic and sporadic forms of pneumonia caused by this organism. It also causes Pontiac fever, a related self-limited upper respiratory tract infection. This organism flourishes in artificial aquatic environments, such as water-cooling towers and within the tubing system of domestic (potable) water supplies. The mode of transmission is either inhalation of aerosolized organisms or aspiration of contaminated drinking water. Legionella pneumonia is common in individuals with some predisposing condition such as cardiac, renal, immunological, or hematologic disease. Organ transplant recipients are particularly susceptible. It can be quite severe, frequently requiring hospitalization, and immunosuppressed patients may have fatality rates of up to 50%. Rapid diagnosis is facilitated by demonstration ofLegionella antigens in the urine or by a positive fluorescent antibody test on sputum samples; culture remains the gold standard of diagnosis.
What are three types of pneumonia dependant on lung location and how do their etiologies differ?
Intra-alveolar
- Lobar: uniform consodiation of part of a lobe or entire lobe - common in community acquired pneumonia, usually bacterial - Strep pneumonia common
- Bronchial - patchy throughout lung, but quite lobular, usually bilateral. common in hospitalized patinets and as terminal illness. pre-existing bronchitis spread to nearby connective lung tissue, usually bacterial
Interstitial
- Interstitial - infection of type I pneumocyte - > alveolar injury -> interstitial pneumonia (more serious), viral origin (think virus could kill Type I pneunocytes, bacteria not as much).
In immunocompromised host
- normal bacterial suspects
- MAC, cytomegalovirus, pneumocystis jiroveci (carinii) - use silver stain
What are the 4 stages of lobar (bacterial origin) pneumonia?
Stage I: congestion = intra-alveolar fluid, few neutrophils, many bacteria
Stage II: red hepatization (think that lung looks like liver when hurt) = inta-alveolar neutrophils with RBCs and fibrin = red alveoli
Stage III: grey hepatization = macrophages replace neutrophils and ingest debris
Stage IV: resolution (but can have complications)
What are some complications of pneumonia?
* lung abcess (ex. Staph aureus + anaerobes) = destruction of pulmonary parenchyma; usually get abcess through aspiration of say infected oral flora, etc
* bacterial dissemination: meningitis, endocarditis, etc
* emphyema = inflammation of pleural cavity
* death
this is why antibiotics are needed - dramatically decrease occurence of these events
What about some viral causes of pneumonia?
Influenza Infections
The genome of influenza virus is composed of eight helices of single-stranded RNA, with 3 types (A, B, C) and subtypes (H1-H3, N1-N2).
Influenza viruses of type A infect humans, pigs, horses, and birds and are the major cause of pandemic and epidemic influenza infections.
Epidemics of influenza occur through mutations of the hemagglutinin and neuraminidase that allow the virus to escape most host antibodies (antigenic drift). Pandemics, which are longer and more widespread than epidemics, may occur when both the hemagglutinin and the neuraminidase are replaced through recombination of RNA segments with those of animal viruses, making all individuals susceptible to the new influenza virus (antigenic shift).
Influenza virus types B and C, which do not show antigenic drift or shift, infect mostly children, who develop antibodies that prevent reinfection. Rarely, influenza virus may cause interstitial myocarditis or, after aspirin therapy, Reye syndrome.
Avian influenza refers to strains of influenza which primarily infect birds. One such strain with the antigenic type H5N1 is of great concern because infection is frequently lethal in humans (approximately 60%) and since 2003 the virus is spreading throughout the world in wild and domestic birds.
Morphology. Viral upper respiratory infections are marked by mucosal hyperemia and swelling with a predominantly lymphomonocytic and plasmacytic infiltration of the submucosa accompanied by overproduction of mucus secretions. The swollen mucosa and viscous exudate may plug the nasal channels, sinuses or the Eustachian tubes, and lead to suppurative secondary bacterial infection.
In laryngotracheobronchitis and bronchiolitis there is vocal cord swelling and abundant mucus exudation. Impairment of bronchociliary function invites bacterial superinfection with more marked suppuration. Plugging of small airways may give rise to focal lung atelectasis. In the more severe bronchiolar involvement widespread plugging of secondary and terminal airways by cell debris, fibrin, and inflammatory exudate may, when prolonged, cause organization and fibrosis, resulting in obliterative bronchiolitis and permanent lung damage.
Human Metapneumovirus (MPV)
Human MPV, a paramyxovirus discovered in 2001, is found worldwide and is associated with upper and lower respiratory tract infections, most commonly in young children, elderly subjects, and immunocompromised patients. Human MPV can cause severe infections such as bronchiolitis and pneumonia and is responsible for 5% to 10% of hospitalizations and 12% to 20% of outpatient visits of children suffering from acute respiratory tract infections. Such infections are clinically indistinguishable from those caused by human respiratory syncytial virus. Molecular methods such as reverse transcriptase–PCR are the preferred diagnostic modality because of fastidious growth in cell culture. No commercial treatments are yet available for human MPV, although ribavirin has shown activity both in vitro and in animal models.
Severe Acute Respiratory Syndrome (SARS)
SARS first appeared in November 2002 in the Guangdong Province of China and subsequently spread to Hong Kong, Taiwan, Singapore, Vietnam, and Toronto, where large outbreaks also occurred.[132]
After an incubation period of 2 to 10 days, SARS begins with a dry cough, malaise, myalgias, fever, and chills. A third of patients improve and resolve the infection, but the rest progress to severe respiratory disease with shortness of breath, tachypnea, and pleurisy, and nearly 10% of patients die from the illness, for which there is no specific treatment.
SARS virus differs from previously known coronaviruses in that it infects the lower respiratory tract and spreads throughout the body.
SARS can be diagnosed either by detection of the virus by PCR or by detection of antibodies to the virus. Levels of the virus are low initially and peak 10 days after onset of illness, so testing of different specimens (respiratory secretions, blood, and stool) collected on several days may be needed to detect the virus. Detection of antibodies specific for the SARS virus is a very sensitive and specific test; however, patients may not have a measurable antibody response for up to 28 days after infection.
What bacteria cause TB? What are their general features?
Mycobacterium tuberculosis (lungs as primary) - most common, mycobacterium bovis (GI, in pasteurized milk). Extremely rarely M. africanum and M.microti.
Tuberculosis is mainly a disease of the elderly, the urban poor, and people with AIDS. Certain disease states also increase the risk: diabetes mellitus, chronic lung disease (particularly silicosis), chronic renal failure, malnutrition, alcoholism, and immunosuppression.
It is important that infection with M. tuberculosis be differentiated from disease. Infection is the presence of organisms, which may or may not cause clinically significant disease. Most infections are acquired by person-to-person transmission of airborne organisms from an active case to a susceptible host. In most people primary tuberculosis is asymptomatic, although it may cause fever and pleural effusion. Generally, the only evidence of infection, if any remains, is a tiny, fibrocalcific nodule at the site of the infection. Viable organisms may remain dormant in such lesions for decades. If immune defenses are lowered, the infection may reactivate to produce communicable and potentially life-threatening disease.
Infection typically leads to the development of delayed hypersensitivity to M. tuberculosis antigens, which can be detected by the tuberculin (Mantoux) skin test. About 2 to 4 weeks after infection, intracutaneous injection of purified protein derivative of M. tuberculosis induces a visible and palpable induration that peaks in 48 to 72 hours. A positive tuberculin test result signifies T cell–mediated immunity to mycobacterial antigens. It does not differentiate between infection and disease. False-negative reactions may occur in the setting of certain viral infections, sarcoidosis, malnutrition, Hodgkin lymphoma, immunosuppression, and (notably) overwhelming active tuberculous disease. False-positive reactions may result from infection by atypical mycobacteria or prior vaccination with BCG (Bacillus Calmette-Guerin), an attenuated strain of M. bovis that is used as a vaccine in some countries.
Bacteria in the genus Mycobacterium are slender, aerobic rods that grow in straight or branching chains. Mycobacteria have a unique waxy cell wall composed of mycolic acid, which makes them** acid fast**, meaning they will retain stains even on treatment with a mixture of acid and alcohol. Mycobacteria are weakly Gram positive. Show well on Ziehl-Neelsen stain.
Pathogenesis of TB?
- M. tuberculosis enters macrophages by endocytosis
- Once inside the macrophage, M. tuberculosis organisms replicate within the phagosome by blocking fusion of the phagosome and lysosome (so don’t get digested) Thus, during the earliest stage of primary tuberculosis (<3 weeks) in the nonsensitized individual, bacteria proliferate in the pulmonary alveolar macrophages and airspaces, resulting in bacteremia and seeding of multiple sites.Despite the bacteremia, most people at this stage are asymptomatic or have a mild flulike illness.
- About 3 weeks after infection, a T-helper 1 (TH1) response is mounted that activates macrophages to become bactericidal. Differentiation of TH1 cells happens.
- Mature TH1 cells, both in lymph nodes and in the lung, produce IFN-γ. INF-γ is the critical mediator that enables macrophages to contain the M. tuberculosis infection. IFN-γ stimulates formation of the phagolysosome in infected macrophages, exposing the bacteria to an inhospitable acidic environment. IFN-γ also stimulates expression of inducible nitric oxide synthase, which produces nitric oxide, capable of destroying several mycobacterial constituents, from cell wall to DNA.
- In addition to stimulating macrophages to kill mycobacteria, the TH1 response orchestrates the formation of granulomas and caseous necrosis.
In summary, immunity to M. tuberculosis is primarily mediated by TH1 cells, which stimulate macrophages to kill the bacteria. This immune response, while largely effective, comes at the cost of hypersensitivity and accompanying tissue destruction. Reactivation of the infection or re-exposure to the bacilli in a previously sensitized host results in rapid mobilization of a defensive reaction but also increased tissue necrosis. Just as hypersensitivity and resistance are correlated, so, too, the loss of hypersensitivity (indicated by tuberculin negativity in a previously tuberculin-positive individual) may be an ominous sign that resistance to the organism has faded.
What is primary and secondary TB?
What other scary TB effects are possible?
Primary Tuberculosis.
In countries where infected milk has been eliminated, primary tuberculosis almost always begins in the lungs. Typically, the inhaled bacilli implant in the distal airspaces of the lower part of the upper lobe or the upper part of the lower lobe, usually close to the pleura. As sensitization develops, a 1- to 1.5-cm area of gray-white inflammation with consolidation emerges, known as the Ghon focus. In most cases, the center of this focus undergoes caseous necrosis. Tubercle bacilli, either free or within phagocytes, drain to the regional nodes, which also often caseate. This combination of parenchymal lung lesion and nodal involvement is referred to as the Ghon complex. During the first few weeks there is also lymphatic and hematogenous dissemination to other parts of the body. In approximately 95% of cases, development of cell-mediated immunity controls the infection. Hence, the Ghon complex undergoes progressive fibrosis, often followed by radiologically detectable calcification (Ranke complex), and despite seeding of other organs, no lesions develop.
Immunocompromised people do not form the characteristic granulomas (not enough CD4s and thus T cells to work their magic).
Secondary Tuberculosis. The initial lesion is usually a small focus of consolidation, less than 2 cm in diameter, within 1 to 2 cm of the apical pleura. Such foci are sharply circumscribed, firm, gray-white to yellow areas that have a variable amount of central caseation and peripheral fibrosis. In immunocomptetent individuals, the initial parenchymal focus undergoes progressive fibrous encapsulation, leaving only fibrocalcific scars. Histologically, the active lesions show characteristic coalescent tubercles with central caseation. Localized, apical, secondary pulmonary tuberculosis may heal with fibrosis either spontaneously or after therapy, or the disease may progress and extend along several different pathways.
Progressive pulmonary tuberculosis may ensue in the elderly and immunosuppressed. The apical lesion expands into adjacent lung and eventually erodes into bronchi and vessels.
Erosion of blood vessels results in hemoptysis. With adequate treatment the process may be arrested, although healing by fibrosis often distorts the pulmonary architecture. The cavities, now free of inflammation, may persist or become fibrotic.
If the treatment is inadequate or if host defenses are impaired, the infection may spread via airways, lymphatic channels, or the vascular system.
Miliary pulmonary diseaseoccurs when organisms draining through lymphatics enter the venous blood and circulate back to the lung. Individual lesions are either microscopic or small, visible (2-mm) foci of yellow-white consolidation scattered through the lung parenchyma (the adjective “miliary” is derived from the resemblance of these foci to millet seeds). With progressive pulmonary tuberculosis, the pleural cavity is invariably involved, and serous pleural effusions, tuberculous empyema, or obliterative fibrous pleuritis may develop.
Endobronchial, endotracheal, and laryngeal tuberculosis may develop by spread through lymphatic channels or from expectorated infectious material.
Systemic miliary tuberculosis occurs when bacteria disseminate through the systemic arterial system. Miliary tuberculosis is most prominent in the liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes, and epididymis, but could involve any organ
Isolated tuberculosis may appear in any of the organs or tissues seeded hematogenously and may be the presenting manifestation. Organs that are commonly involved include the meninges (tuberculous meningitis), kidneys (renal tuberculosis), adrenals (formerly an important cause of Addison disease), bones (osteomyelitis), and fallopian tubes (salpingitis). When the vertebrae are affected, the disease is referred to as Pott disease. Paraspinal “cold” abscesses in these patients may track along tissue planes and present as an abdominal or pelvic mass.
